Abstract

Treating elderly patients with two low-dose mTOR inhibitors that selectively block TORC1 led to a decrease in infection rates.

Inhibiting the mechanistic target of rapamycin (mTOR) signaling pathway has extended lifespan in all species studied and boosted immune function in aged mice. mTOR signals via target of rapamycin complex 1 (TORC1) and TORC2; TORC1 inhibition has beneficial effects but inhibiting TORC2 can shorten lifespan. Mannick et al. report results of a phase 2a randomized, placebo-controlled clinical trial of two synergistic low-dose TORC1 inhibitors on immune function in 264 patients over 65 years of age. Patients treated for 6 weeks with a low-dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor that selectively targeted TORC1 had increased serologic responses after vaccination for influenza and suffered from substantially fewer infections over the subsequent year than patients treated with placebo. This included reductions in respiratory infections, a key source of morbidity in older individuals. RNA sequencing studies showed that treated patients had increased expression of type I interferon induced genes in peripheral blood, although levels of inflammatory cytokines [interleukin-6 (IL-6), interferon-γ (IFN-γ), tumor necrosis factor–α (TNFα), IL-18] were no different from those of placebo treated patients. Studies in rats showed that the combination of the two inhibitors synergistically targeted multiple downstream targets of TORC1, producing a more effective therapeutic blockade than either agent alone. The drugs were used at very low doses, between 3- to 120-fold lower than levels used in organ transplant and oncology patients; higher doses of mTOR inhibitors blocked T cell proliferation and had the opposite effect of increasing infections. The course of treatment was short but effective–6 weeks of therapy measurably reduced infections over a year. TORC1 inhibition may boost immune responses by several mechanisms. RAD001 monotherapy reduced the number of exhausted, programmed cell death protein 1–expressing T cells in a prior human trial. In the current trial, the low-dose drug combination increased expression of type I interferon induced genes that may boost antiviral immunity. Taken together, these studies show that short-term, low-dose treatment of older individuals with a synergistic combination of TORC1 inhibitors can measurably improve immune function and may be a promising approach for invigorating immune responses in older individuals.